Molecular signatures in post mortem brain tissue of individuals at high risk for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative condition characterized pathologically by neuritic plaques and neurofibrillary tangles. The objective in the present transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases who were non-APOE4 carriers (called the APOE3 group) and 13 cases who were APOE4 carriers. Because APOE genotype is the major genetic risk factor for late onset AD, the former group was at low risk for development of the disease and latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low-risk) and APOE4 (high-risk) genotype groups. We identified 70 transcripts that differed significantly between the groups and several Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation, and cell-cycle re-entry. Using RT-qPCR, we validated multiple findings. Using pathway analyses we then found that these molecules comprised a network with multiple connections with each other and with APP and MAPT. Our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.